Process for producing oxazole compound

ABSTRACT

The present invention relates to a method for producing a compound of the formula [7]wherein R1 is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R2 is a lower alkyl or a halogenated lower alkyl and R3 is a halogen atom or a hydrogen atom. The method of the present invention includes reacting compound [1] with thionyl chloride to give compound [2] and obtaining the objective compound [7] at a high yield via intermediate [5], and is utilizable for industrial production.

This application is a 371 of PCT/JP99/04753 filed Sep. 1, 1999.

TECHNICAL FIELD

The present invention relates to a novel production method of an oxazolecompound of the formula [7] having a selective inhibitory action oncyclooxygenase-2 (COX-2)

wherein R¹ is an optionally substituted cycloalkyl group, an optionallysubstituted aryl group or an optionally substituted heterocyclic group,R² is a lower alkyl or a halogenated lower alkyl, and R³ is a halogenatom or a hydrogen atom. The present invention also relates to a methodfor producing intermediates for the production of a compound of theabove-mentioned formula [7].

BACKGROUND ART

The above-mentioned compound [7], which selectively inhibitscyclooxygenase-2 (COX-2), is useful as, for example, an antiinfammatoryagent. The production method of compound [7] has been already disclosedin the specification of W096/ 19463.

However, the conventional production methods require many treatmentsteps and the yields of the final product and intermediates therefor arenot entirely satisfactory. In addition, the reagent, solvent and thelike to be used in each step suffice for use only at laboratory levelsand many of them are problematically impractical and cannot be used inindustrial production.

DISCLOSURE OF THE INVENTION

The present inventors have studied respective steps in detail andimproved them. To be specific, they considered the production method(hereinafter to be referred to as method A) disclosed in W096/ 19463,which is most similar to the present invention.

According to the method A, compound [7′], which is one of the objectivecompounds of the present invention, is produced by the following Steps1-4.

Step 1

According to method A, compound [1′] is reacted with ethylchlorocarbonate in ethyl acetate in the presence of triethylamine togive compound [2′]. When ethyl chlorocarbonate is used as a reagent inthis step, ethanol is generated as a by-product and decomposes compound[2′]. To prevent this, a complicated post-treatment such as desaltingfiltration and concentration is needed after the main reaction,cyclization. Thus, method A is associated with a complicatedpost-treatment and lower yield of compound [2′] due to the generation ofthe by-product. The present inventors considered using economicalthionyl chloride instead of ethyl chlorocarbonate to solve this problem.As a result, they have found that the use of thionyl chlorideobliterates the above-mentioned complicated post-treatment andgeneration of the by-product, which has led to an improvement in theyield. It has been also found that the unstable compound [2′] can beused in the next step without isolation or purification. Theseimprovements have achieved an increase in the yield.

Step 2

In method A, compound [2′] is reacted with compound [3′] in atetrahydrofuran suspension of magnesium chloride in the presence oftriethylamine to give compound [4′]. Tetrahydrofuran used as a reagentand solvent in this step is not a most suitable solvent in terms ofcost, when industrially used in a large amount. Thus, the presentinventors have studied solvents to find out a solvent economical andsuitable for industrial production, as well as from the aspect of animproved yield. Consequently, they have found that ethyl acetate, whichis recited in the specification of WO96/ 19463 as a general example butis not specifically disclosed as an example, can be used to conduct thisreaction similarly. This change of solvent offers merits of not only lowcost but omission of concentration of the reaction solvent beforeextraction in the next step (Step 3). This has offered a simultaneousresolution to the problems of reduction of cost and increase in yield.In addition, they have found that the unstable compound [4′] can be usedin the next step without isolation or purification. These improvementsresulted in an increased yield.

Step 3

In method A, hydrochloric acid is added to compound [4′] intrahydrofuran to allow hydrolysis and decarboxylation. Subsequently,compound [5′] is obtained through post-treatment of concentration of thereaction solvent (tetrahydrofuran), extraction, concentration of theextraction solvent and the like. The present inventors changedtetrahydrofuran, the solvent used in the previous step (Step 2), toethyl acetate and conducted Step 3 in ethyl acetate, whereby they havesucceeded in omitting a step for concentration of tetrahydrofuran beforeextraction. This has led to the improved yield of compound [5′].

When compared in the yields of Compound [5′] from compound [1′], it was67.7% by method A but 84.7% by the present invention, thus achieving a17% increase in the yield.

Step 4

In method A, compound [5′] is reacted with chlorosulfonic acid inchloroform to give compound [6′]. Further, by reacting this compoundwith aqueous ammonia in tetrahydrofuran without isolation, objectivecompound [7′] is obtained. The solvent used here is chloroform, whichhas strong toxicity and is problematic for industrial use. The presentinventors have overcome this problem by the use of a method generallyexemplified in the specification of WO96/19463 but not specificallyshown as an example. Surprisingly, the reaction was found to proceed assmoothly as when chloroform was used, even without a solvent.

The method A is not satisfactory in terms of the yield of the objectivecompound [7′]. According to method A, compound [7′] is obtained througha post-treatment of concentration of the reaction solvent(tetrahydrofuran), extraction, concentration of the extraction solventand the like. Like Step 2, the present inventors changed the solvent foramidation from tetrahydrofuran to ethyl acetate to omit concentration oftetrahydrofuran before extraction.

This has led to the elimination of problems associated with the priorart technique, and the yield of compound [7′] from compound [5′] wasincreased by about 5% from 77.2% to 82.0%.

As mentioned above, the present inventors studied the problems in eachstep in detail with the aim of improving the yield of the objectivecompound and establishing the method capable of affording industrialproduction, and they have found that the use of the above-mentionedsolvent, reagent and the like in each step results in the production ofthe objective compound at a high yield and also an industriallypractical production method, which resulted in the completion of thepresent invention.

Accordingly, the present invention provides the following (1) to (9).

(1) A production method of an oxazole compound of the formula [7]

wherein R¹ is an optionally substituted cycloalkyl group, an optionallysubstituted aryl group or an optionally substituted heterocyclic group,R² is a lower alkyl or a halogenated lower alkyl and R³ is a halogenatom or a hydrogen atom, comprising reacting a compound of the formula[1]

wherein R¹ and R² are as defined above, with thionyl chloride in aninert solvent in the presence of a base, to give an oxazolone compoundof the formula [2]

wherein R¹ and R² are as defined above, subsequently reacting thiscompound with a compound of the formula [3]

wherein R³ is as defined above and X is a halogen atom, in ethyl acetatein the presence of a magnesium salt and a base to give a compound of theformula [4]

wherein R¹, R² and R³ are as defined above, subjecting this compound tohydrolysis and decarboxylation with an acid to give a compound of theformula [5]

wherein R¹, R² and R³ are as defined above, subjecting this compound tocyclization and sulfonation with a sulfonating agent and chlorinationwith thionyl chloride to give a compound of the formula [6]

wherein R¹, R² and R³ are as defined above, and subjecting this compoundto amidation in ethyl acetate with aqueous ammonia

(2) The method of (1) wherein R¹ is a cycloalkyl, R² is a lower alkyl,and R³ is a halogen atom.

(3) The method of (1) wherein R¹ is a cyclohexyl, R² is a methyl, and R³is a fluorine atom.

(4) A production method of an acetophenone compound of the formula [5]

wherein R¹ is an optionally substituted cycloalkyl group, an optionallysubstituted aryl group or an optionally substituted heterocyclic group,R² is a lower alkyl or a halogenated lower alkyl and R3 is a halogenatom or a hydrogen atom, comprising reacting a compound of the formula[1]

wherein R¹ and R² are as defined above, with thionyl chloride in aninert solvent in the presence of a base to give an oxazolone compound ofthe formula [2]

wherein R¹ and R² are as defined above, sequentially reacting thiscompound with a compound of the formula [3]

wherein R³ is as defined above and X is a halogen atom, in ethyl acetatein the presence of a magnesium salt and a base to give a compound of theformula [4]

wherein R¹, R² and R³ are as defined above, and subjecting this compoundto hydrolysis and decarboxylation with an acid.

(5) The method of (4) wherein R¹ is a cycloalkyl, R² is a lower alkyl,and R³ is a halogen atom.

(6) The method of (4) wherein R¹ is a cyclohexyl, R² is a methyl, and R³is a fluorine atom.

(7) A production method of an oxazole compound of the formula [7]

wherein R¹ is an optionally substituted cycloalkyl group, an optionallysubstituted aryl group or an optionally substituted heterocyclic group,R² is a lower alkyl or a halogenated lower alkyl and R³ is a halogenatom or a hydrogen atom, comprising subjecting a compound of the formula[5]

wherein R¹, R² and R³ are as defined above, to cyclization andsulfonation with a sulfonating agent, and chlorination with thionylchloride to give a compound of the formula [6]

wherein R¹, R² and R³ are as defined above, and then subjecting thiscompound to amidation in ethyl acetate with aqueous ammonia.

(8) The method of (7) wherein R¹ is a cycloalkyl, R² is a lower alkyl,and R3 is a halogen atom.

(9) The method of (7) wherein R¹ is a cyclohexyl, R² is a methyl, and R³is a fluorine atom.

Each substituent used in the present specification are defined asfollows.

The cycloalkyl group is that having 3 to 8 carbon atoms, which isspecifically exemplified by cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. Preferred is cycloalkyl grouphaving 5 to 7 carbon atoms. Specific examples thereof includecyclopentyl, cyclohexyl and cycloheptyl, where particularly preferred iscyclohexyl.

The heterocyclic group is a 5- or 6-membered aromatic heterocycle,saturated heterocycle, unsaturated heterocycle, or condensed heterocyclewherein such heterocycle and a benzene ring or cyclohexane ring arecondensed, which has, as an atom constituting the ring, 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, besidescarbon atom. Specific examples thereof include thienyl, furyl, pyrrolyl,imnidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,morpholino, morpholinyl, piperazinyl, piperidyl, pyranyl, thiopyranyl,pyridyl, benzothienyl, benzofuranyl, indolyl, 4,5,6,7-tetrahydroindolyl,4,5,6,7-tetrahydrobenzothienyl, 4,5,6,7-tetrahydrobenzofuranyl and thelike. Preferred are thienyl, furyl, pyrrolyl, morpholino, morpholinyl,piperazinyl and piperidyl, and particularly preferred is thienyl.

The aryl group is, for example, phenyl, naphthyl, biphenylyl and thelike, with preference given to phenyl.

The “optionally substituted” means that the group may be substituted by1 to 3 substituents which may be the same or different. The position ofthe substituent is optional and subject to no particular limitation.Specific examples thereof include lower alkyl such as methyl, ethyl,propyl, isopropyl, butyl, tert-butyl and the like; hydroxy; lower alkoxysuch as methoxy, ethoxy, propoxy, butoxy and the like; halogen atom suchas fluorine, chlorine, bromine and the like; nitro; cyano; acyl (e.g.,formyl, or lower alkylcarbonyl such as acetyl, propionyl and the like);acyloxy such as formyloxy, acetyloxy, propionyloxy and the like (acylmoiety being as defined above); mercapto; lower alkylthio such asmethylthio, ethylthio, propylthio, butylthio, isobutylthio and the like;amino; lower alkylamino such as methylamino, ethylamino, propylamino,butylamino and the like; di(lower)alkylamino such as dimethylamino,diethylamino, dipropylamino, dibutylamino and the like; carboxy; loweralkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyland the like; amido; trifluoromethyl; lower alkylsufonyl such asmethylsulfonyl, ethylsulfonyl and the like; aminosulfonyl; lowercycloalkyl such as cyclopentyl, cyclohexyl and the like; phenyl; andacylamino such as acetamido, propionamido and the like (acyl moietybeing as defined above), with preference given to hydroxy, lower alkyl,lower alkoxy, mercapto, lower allkylthio, halogen atom, tifluoromethyl,lower alkylcarbonyl, lower alkoxycarbonyl and acylamino. As used herein,by lower is meant that the number of carbon atoms is preferably 1 to 6,more preferably 1 to 4.

More specifically, the “optionally substituted aryl group” means arylgroup, particularly phenyl group optionally substituted by halogen atom,hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl, aminosulfonyland the like. Specific examples thereof include phenyl, fluorophenyl,methylphenyl, methoxyphenyl, methylsulfonylphenyl, arninosulfonylphenyland the like, preferably phenyl and 4-fluorophenyl.

The “optionally substituted heterocyclic group” is heterocyclic groupoptionally substituted by halogen atom, hydroxy, lower alkyl, loweralkoxy, lower alkylsulfonyl, aminosulfonyl and the like, with preferencegiven to thienyl, furyl, 5-methylthienyl and 5-chlorothienyl.

The “optionally substituted cycloalkyl group” is cycloalkyl groupoptionally substituted by halogen atom, hydroxy, lower alkyl, loweralkoxy, lower alkylsulfonyl, aminosulfonyl and the like, with preferencegiven to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,4methylcyclohexyl, 4-hydroxycyclohexyl, 4-fluorocyclohexyl and the like,particularly preferably cyclohexyl.

The “lower aLkyl” is linear or branched alkyl having 1 to 6 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl,tert-pentyl, hexyl and the like, which is preferably methyl.

The “halogen atom” means chlorine atom, bromine atom, fluorine atom andthe like, with preference given to chlorine atom and fluorine atom. AtR³, it is preferably fluorine atom and at X, it is preferably chlorineatom.

The “halogenated lower allyl” is the above-mentioned lower alkylsubstituted by the above-mentioned halogen atom. Specific examplesthereof include fluoromethyl, chloromethyl, bromomethyl, iodomethyl,difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl,fluoroethyl, chloroethyl, difluoroethyl, dichloroethyl, trifluoroethyl,trichloroethyl, tetrachloroethyl, pentafluoroethyl, fluoropropyl and thelike, with preference given to fluoromethyl, chloromethyl,dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl.

The “inert solvent” means ethyl acetate, tetrahydrofuran, toluene,dichloromethane and the like, preferably ethyl acetate.

The “base” is a tertiary amine such as triethylamine, pyridine,N-methylmorpholine and the like; secondary amine such as diethylamine,diisopropylamine and the like; and inorganic base such as potassiumcarbonate, sodium carbonate and the like, with preference given totertiary amine, which is more preferably triethylarine.

The “magnesium salt” means anhydrous magnesium chloride, anhydrousmagnesium bromide and the like, which is preferably anhydrous magnesiumchloride.

The “acid” means hydrochloric acid, oxalic acid, diluted sulfuric acid,phosphoric acid and the like, which is preferably hydrochloric acid.

The “sulfonating agent” means chlorosulfonic acid, anhydrous sulfuricacid, concentrated sulfuric acid, fuming sulfuric acid and the like,which is preferably chlorosulfonic acid.

The production method of oxazole compound of the formula [7] isdescribed in detail in the following.

wherein R¹, R², R³ and X are as defined above.

General Production Method

Step 1

Compound [1] is reacted with thionyl chloride in an inert solvent in thepresence of a base to give compound [2].

The inert solvent to be used for the reaction is ethyl acetate,tetrahydrofuran, toluene, dichloromethane and the like, which ispreferably ethyl acetate.

Specific examples of the base include tertiary amine such astriethylamine, pyridine, N-methylmorpholine and the like; secondaryamine such as diethylamine, diisopropylamine and the like; and inorganicbase such as potassium carbonate, sodium carbonate and the like, withpreference given to tertiary amine, which is more preferablytriethylamine.

The reaction temperature is −20° C. to 20° C., preferably −10° C. to 0°C.

The reaction time is 0.5-10 hours, preferably 0.5-2 hours.

When this reaction is carried out, the reaction preferably proceedsunder an inert gas atmosphere (e.g., nitrogen) to prevent reduction inthe yield due to contamination with water.

The obtained compound [2] can be used in the next reaction withoutisolation.

Step 2

Compound [2] is reacted with compound [3] in ethyl acetate in thepresence of a magnesium salt and a base to give compound [4].

As the magnesium salt, anhydrous magnesium chloride, anhydrous magnesiumbromide and the like, preferably anhydrous magnesium chloride, can beused.

Examples of the base include tertiary amine such as triethylamine,pyridine, N-methylmorpholine and the like; secondary amine such asdiethylamine, diisopropylamine and the like; and inorganic base such aspotassium carbonate, sodium carbonate and the like, with preferencegiven to tertiary amine, which is more preferably triethylamine.

The reaction temperature is −20° C. to 20° C., preferably 0° C. to 10°C.

The reaction time is 1-20 hours, preferably 6-15 hours.

This reaction is desirably carried out under an inert gas atmosphere,such as nitrogen as in Step 1, to prevent reduction in the yield due tocontamination with water.

In this step, ether such as tetrahydrofuran, diethyl ether and the like,preferably tetrahydrofuran, is used as a reagent, which ensures smoothprogress of the reaction. Ether is added in 2-5 equivalents, preferably2 equivalents, relative to compound [2].

The obtained compound [4] can be used in the next reaction withoutisolation.

Step 3

Compound [4] is subjected to hydrolysis and decarboxylation with an acidto give compound [5].

This reaction preferably proceeds in a mixed solvent of ethyl acetateand water.

The acid to be used is exemplified by hydrochloric acid, oxalic acid,diluted sulfuric acid, phosphoric acid and the like, which is preferablyhydrochloric acid.

The reaction temperature is −20° C. to 100° C., preferably 35° C. to 45°C.

The reaction time is 1-20 hours, preferably 1-3 hours.

Step 4

Compound [5] is subjected to cyclization and sulfonation with asulfonating agent, and chlorination with thionyl chloride to givecompound [6]. Sequentially, the product is, without isolation, reactedwith aqueous ammonia in ethyl acetate to give the objective compound[7].

The reactions of cyclization and sulfonation are preferably carried outwithout solvent.

The sulfonating agent to be used is exemplified by chlorosulfonic acid,anhydrous sulfuric acid, concentrated sulfuric acid, fuming sulfuricacid and the like, which is preferably chlorosulfonic acid.

The temperature of the reaction to obtain compound [6] from compound [5]is 0° C.-200° C., preferably 75° C.-95° C. The time of the reaction ofcyclization and sulfonation is 1-10 hours, preferably 2-5 hours. Thereaction time of chlorination is 0.5-10 hours, preferably 0.5-5 hours.

In the reaction to obtain compound [6] from compound [5], the reactionis desirably carried out under an inert gas atmosphere, such as nitrogenas in Step 1, to prevent reduction in the yield due to contaminationwith water.

The temperature of the reaction to obtain compound [7] from compound [6]is −20° C. to 200° C., preferably −10° C. to 10° C. The reaction time is1-24 hours,preferably 1-3 hours.

EXAMPLES Example 1

2-N-Acetylamino-2-cyclohexyl-3′-fluoroacetophenone (production method ofcompound [5] wherein R¹=cyclohexyl, R²=methyl, R³=3-fluoro)

DLN-Acetyl-2-cyclohexylglycine (60.0 g) was suspended in ethyl acetate(420 mL) under a nitrogen atmosphere, and triethylamine (45.7 g) wasadded thereto for dissolution. Thionyl chloride (37.6 g), and thentriethylamine (106.6 g) were added dropwise under cooling in such amanner that the inside temperature did not exceed 0° C. After thecompletion of the dropwise addition, the mixture was stirred at −10° C.to 0° C. for not less than 30 minutes to give a mixture of4-cyclohexyl-2-methyl-5-oxazolone in ethyl acetate.

To this mixture of 4-cyclohexyl-2-methyl-5-oxazolone in ethyl acetatewas added, under a nitrogen atmosphere, a mixture of ethyl acetate (120mL) and tetrahydrofuran (43.4 g) added with anhydrous magnesium chloride(28.7 g), and the mixture was stirred at 0° C.-10° C. for 1 hour ormore. Thereto was added dropwise 3-fluorobenzoyl chloride (47.7 g) at 0°C.-10° C. and the mixture was stirred at 0° C.-10° C. for 6 hours ormore to give a mixture of4-cyclohexyl-4-(3-fluorobenzoyl)-2-methyl-5-oxazolone and ethyl acetate.

To this mixture of 4-cyclohexyl-4-(3-fluorobenzoyl)-2-methyl-5-oxazolonein ethyl acetate were added dropwise 35% hydrochloric acid (72.1 g) andwater (173 mL) in such a manner that the inside temperature did notexceed 45° C. This reaction mixture was stirred at 35° C.-45° C. for onehour or more, cooled to 10° C.-30° C. and allowed to stand still forseparation of layers, and the aqueous layer was removed. The obtainedorganic layer was washed with water (420 mL), 20% aqueous potassiumcarbonate solution (420 g), and 10% brine (420 g). The organic layerobtained by standing still was concentrated to 198 g and the residue wasdissolved by heating, which was followed by addition of heptane (212mL). The inside temperature was cooled to 55° C.-65° C., matured forcrystallization at 55° C.-65° C. for 1 hour or more, cooled to not morethan −10° C. and matured for crystazation at not more than −10° C. forone or more hours. This crystal mixture was filtered and the crystalscollected by filtration were washed with a mixture of ethyl acetate (54mL) and heptane (162 mL) cooled to −10° C. The crystals were dried underreduced pressure to give the title compound (compound [5]; 70.7 g, yield84.7%) as slightly yellow white crystals.

m.p.: 116-118° C.; ¹H-NMR (300 MHz, CDCl₃, TMS): δ0.9-1.3 (5H, m), 1.5(1H, m), 1.6-1.9 (4H, m), 2.07 (3H, s), 5.52 (1H, dd ), 6.27 (1H, br-d),7.31 (1H, td), 7.49 (1H, td), 7.67 (1H, td), 7.79 (1H, br-d) IR (KBr):3282, 2920, 1681, 1637, 1588, 1297 cm⁻¹; MS (FAB+): 278 (MH⁺).

Example 2

5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole(production method of compound [7] wherein R¹=cyclohexyl, R²=methyl,R³=3-fluoro)

2-N-Acetylamino-2-cyclohexyl-3′-fluoroacetophenone (60.0 g) was castportionwise into chlorosulfonic acid (126.1 g) under a nitrogenatmosphere in such a manner that the inside temperature did not exceed20° C. The mixture was stirred at an inside temperature of 75° C.-95° C.for 2 hours or more and thionyl chloride (77.2 g) was added dropwise at75° C.-95° C., which was followed by stirring at 75° C.-95° C. for 30minutes or more. The reaction mixture was cooled to not more than 5° C.and ethyl acetate (180 mL) was added dropwise in such a manner that theinside temperature did not exceed 10° C., which was followed by coolingto not more than 5° C. This reaction mixture was added dropwise to amixture of cooled ethyl acetate-water (120 mL-480 mL; not more than 5°C.) in such a manner that the inside temperature did not exceed 10° C.The container used for the dropwise addition was washed with ethylacetate (60 mL) and water (60 mL), and the reaction mixture and washingwere combined. The mixture was allowed to stand for separation oflayers, and the aqueous layer was removed. The obtained organic layerwas washed with water (300 mL) to give a solution of5-(4-chlorosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole inethyl acetate.

This solution of5-(4-chlorosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole inethyl acetate was cooled to not more than 0° C. and added dropwise to amixture of 25% aqueous ammonia (73.7 g) and ethyl acetate (180 mL)cooled to not more than 0° C. in advance, in such a manner that theinside temperature did not exceed 10° C. The mixture was stirred at −10°C. to 10° C. for not less than 1 hour. To this reaction mixture wasadded 25% brine (226 g) and the mixture was allowed to stand forseparation of layers, and the aqueous layer was removed. The obtainedorganic layer was washed with 25% brine (226 g). The ethyl acetateextract obtained by standing was concentrated and the solvent waschanged to isopropyl alcohol crystallization solvent. This slurry wasdissolved by heating and gradually cooled to 30° C.-50° C. Aftermaturing the crystals at 30° C.-50° C. for not less than 1 hour, themixture was cooled to not more than 10° C. The crystals were matured atnot more than 10° C. for not less than 2 hours. The liquid containingcrystals was filtered, and the crystals were washed with isopropylalcohol (180 mL) cooled to not more than 10° C. and dried under reducedpressure to give the title compound (compound [7]; 60.0 g, yield 82.0%)as white crystals.

m.p.: 166-167° C. ¹H-NMR (300 MHz, CDCl₃, TMS): δ1.3-1.5 (3H, m),1.7-1.9 (7H, m), 2.51 (3H, s), 2.79 (1H, tt, J=3.7, 11.3 Hz ), 5.19 (2H,br-s), 7.36-7.43 (2H, m), 7.94 (1H, t) IR (KBr) : 3342, 3244, 2932,1612, 1344, 1168 cm⁻¹; MS (FAB+): 339 (MH⁺);

INDUSTRIAL APPLICABILITY

As is evident from the foregoing, the present invention can produce adesired compound [7] that selectively inhibits cyclooxygenase-2 (COX-2)extremely efficiently at high yields as compared to conventionalmethods. In addition, the production method of the present invention isa highly practical and industrially very useful production method.

This application is based on application no. 249621/1998 filed in japan,the content of which is incorporated hereinto by reference.

What is claimed is:
 1. A production method of an oxazole compound of theformula [7]

wherein R¹ is an optionally substituted cycloalkyl group, an optionallysubstituted aryl group or an optionally substituted heterocyclic group,R² is a lower allyl or a halogenated lower alkyl and R³ is a halogenatom or a hydrogen atom, comprising reacting a compound of the formula[1]

wherein R¹ and R² are as defined above, with thionyl chloride in aninert solvent in the presence of a base, to give an oxazolone compoundof the formula [2]

wherein R¹ and R² are as defined above, subsequently reacting thiscompound with a compound of the formula [3]

wherein R³ is as defined above and X is a halogen atom, in ethyl acetatein the presence of a magnesium salt and a base to give a compound of theformula [4]

wherein R¹, R² and R³ are as defined above, subjecting this compound tohydrolysis and decarboxylation with an acid to give a compound of theformula [5]

wherein R¹, R² and R³ are as defined above, subjecting this compound tocyclization and sulfonation with a sulfonating agent and chlorinationwith thionyl chloride to give a compound of the formula [6]

wherein R¹, R² and R³ are as defined above, and subjecting this compoundto amidation in ethyl acetate with aqueous ammonia.
 2. The method ofclaim 1, wherein R¹ is a cycloalkyl, R² is a lower alkyl, and R³ is ahalogen atom.
 3. The method of claim 1, wherein R¹ is a cyclohexyl, R²is a methyl, and R³ is a fluorine atom.
 4. A production method of anoxazole compound of the formula [7]

wherein R¹ is an optionally substituted cycloalkyl group, an optionallysubstituted aryl group or an optionally substituted heterocyclic group,R² is a lower alkyl or a halogenated lower alkyl and R³ is a halogenatom or a hydrogen atom, comprising subjecting a compound of the formula[5]

wherein R¹, R² and R³ are as defined above, to cyclization andsulfonation with a sulfonating agent, and chlorination with thionylchloride to give a compound of the formula [6]

wherein R¹, R² and R³ are as defined above, and then subjecting thiscompound to amidation in ethyl acetate with aqueous ammonia.
 5. Themethod of claim 4, wherein R¹ is a cycloalkyl, R² is a lower alkyl, andR³ is a halogen atom.
 6. The method of claim 4, wherein R¹ is acyclohexyl, R² is a methyl, and R³ is a fluorine atom.